Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells

Histone ubiquitination at DNA breaks is required for activation of the DNA damage response (DDR) and DNA repair. How the dynamic removal of this modification by deubiquitinating enzymes (DUBs) impacts genome maintenance in vivo is largely unknown. To address this question, we generated mice deficien...

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Published in:The Journal of experimental medicine Vol. 211; no. 9; p. 1759
Main Authors: Lancini, Cesare, van den Berk, Paul C M, Vissers, Joseph H A, Gargiulo, Gaetano, Song, Ji-Ying, Hulsman, Danielle, Serresi, Michela, Tanger, Ellen, Blom, Marleen, Vens, Conchita, van Lohuizen, Maarten, Jacobs, Heinz, Citterio, Elisabetta
Format: Journal Article
Language:English
Published: United States 25.08.2014
Subjects:
Animals
Carcinogenesis
Cell Proliferation
Cellular Senescence
DNA Breaks, Double-Stranded
DNA Damage - physiology
DNA Repair - physiology
Female
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Histones - metabolism
Homeostasis
Lymphopenia - etiology
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Ubiquitin-Specific Proteases - deficiency
Ubiquitin-Specific Proteases - genetics
Ubiquitin-Specific Proteases - metabolism
Ubiquitination
ISSN:1540-9538, 1540-9538
Online Access:Get more information
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Summary:Histone ubiquitination at DNA breaks is required for activation of the DNA damage response (DDR) and DNA repair. How the dynamic removal of this modification by deubiquitinating enzymes (DUBs) impacts genome maintenance in vivo is largely unknown. To address this question, we generated mice deficient for Ub-specific protease 3 (USP3; Usp3Δ/Δ), a histone H2A DUB which negatively regulates ubiquitin-dependent DDR signaling. Notably, USP3 deletion increased the levels of histone ubiquitination in adult tissues, reduced the hematopoietic stem cell (HSC) reserves over time, and shortened animal life span. Mechanistically, our data show that USP3 is important in HSC homeostasis, preserving HSC self-renewal, and repopulation potential in vivo and proliferation in vitro. A defective DDR and unresolved spontaneous DNA damage contribute to cell cycle restriction of Usp3Δ/Δ HSCs. Beyond the hematopoietic system, Usp3Δ/Δ animals spontaneously developed tumors, and primary Usp3Δ/Δ cells failed to preserve chromosomal integrity. These findings broadly support the regulation of chromatin ubiquitination as a key pathway in preserving tissue function through modulation of the response to genotoxic stress.
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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20131436